Project Summary/Abstract The orphan G protein-coupled receptor GPR151 has a distinctive distribution pattern in mammalian brains, with highly specific enrichment in a small bilateral brain structure known as the habenula complex. This structure sends projections to the dopaminergic striatum and receives inputs from the limbic forebrain, modulating cross-talk between these brain regions. It is therefore ideally located, both anatomically and functionally, to regulate emotional, motivational and cognitive behaviors. Consequently, it is believed that the habenula plays a critically important role in the pathophysiology of neuropsychiatric disorders such as schizophrenia, depression and drug dependence. The restricted and unique brain expression pattern of GPR151 suggests a role for this receptor in regulating the habenula complex and thus affecting such disorders. In this proposal we will implement and miniaturize a HTS-compatible cell-based functional assay to facilitate the identification of potent GPR151-selective small molecule molecular probes. These molecules will then be optimized and used to interrogate GPR151's role in regulating the habenula complex and the impact of GPR151 modulation upon both normal physiological processes and disease states.